Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects

Abstract

PurposeVerinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy adult males.Subjects and methodsThis was a Phase I, randomized, double-blind, placebo-controlled, single and multiple ascending dose study. Panels of eight male subjects received a single oral dose of verinurad or placebo in either a fasted or fed state; panels of 10–12 male subjects received ascending doses of once-daily verinurad or placebo in a fasted state for 10 days. Serial blood and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs).ResultsA total of 81 adult males completed the study. Following single doses of verinurad, maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) increased in a dose-proportional manner; Cmax occurred at 0.5–0.75 hours and 1.25 hours in the fasted and fed states, respectively. Food decreased AUC by 23% and Cmax by 37%−53%. There was a modest accumulation of verinurad following multiple daily doses. Verinurad reduced serum urate levels by up to 62% (40 mg, single dose) and 61% (10 mg, multiple dose). The increase in urinary excretion of uric acid was greatest in the first 6 hours after dosing and was still evident ≥24 hours for verinurad doses ≥2 mg. Verinurad was well tolerated at all doses. No serious AEs, severe AEs, discontinuations due to AEs, or clinically significant laboratory or ECG abnormalities were reported.ConclusionSingle and multiple doses of verinurad were well tolerated, absorption was rapid, and exposure was dose proportional. Verinurad increased urinary uric acid elimination and resulted in sustained reductions in serum urate. These data support further clinical evaluation of once-daily verinurad as a treatment for gout.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Concomitant Administration of Verinurad and Febuxostat in Healthy Male Volunteers

“…Achieving sUA levels below recommended targets may lead to improved outcomes such as lower gout flare incidence and/or more rapid tophus area reduction. Similar steady-state results have been reported previously for verinurad 19 as well as for lesinurad. Consistent with its mechanism of action to reduce the production of urate, febuxostat reduced the urinary excretion of uric acid compared to baseline in the current study.…”

Pharmacokinetics, Pharmacodynamics, and Tolerability of Concomitant Multiple Dose Administration of Verinurad (RDEA3170) and Allopurinol in Adult Male Subjects With Gout

“…Analytical methodology for the quantitation of verinurad in urine samples has been described previously . Urine samples were prepared by dilution and quantified using high performance liquid chromatography‐mass spectrometry.…”

“…Verinurad, a selective next‐generation reabsorption inhibitor, demonstrated high potency in inhibiting URAT1 and has shown significant serum uric acid lowering in humans at doses as low as 2.5 mg . The potency and pharmacokinetic properties of verinurad may enable it to be administered at a low dose that could potentially lessen drug‐drug interactions (DDIs) in patients with gout, many of whom also receive treatment for 1 or more comorbidities.…”

“…Elevated urinary uric acid concentrations and low rates of serum creatinine (sCr) elevation have been observed with verinurad monotherapy . In contrast, an xanthine oxidase inhibitors reduces urinary uric acid excretion by inhibiting urate production .…”

“…The clinical trial experience with lesinurad and other urate-lowering agents has demonstrated that achieving serum uric acid levels below recommended targets may lead to improved outcomes (eg, lower gout flare incidence, more rapid tophus area reduction). [12][13][14][15][16] Verinurad, a selective next-generation reabsorption inhibitor, demonstrated high potency in inhibiting URAT1 17 and has shown significant serum uric acid lowering in humans at doses as low as 2.5 mg. 18 The potency and pharmacokinetic properties of verinurad may enable it to be administered at a low dose that could potentially lessen drug-drug interactions (DDIs) in patients with gout, many of whom also receive treatment for 1 or more comorbidities.…”